We have recently established that the gene causing von Recklinghausen's neurofibromatosis (VRNF) is linked to the nerve growth factor receptor on chromosome 17q12 17q22. We propose to isolate the VRNF defect after precisely defining its position by genetic linkage analysis with polymorphic DNA markers. Using chromosome 17 specific libraries, we will generate additional markers closer to, and flanking the VRNF gene. After excluding the possibility of non-allelic genetic heterogeneity in VRNF, these markers should be applicable to prenatal or presymptomatic diagnosis of the disorder. Candidate genes mapping to the region on chromosome 17 containing the VRNF defect will be tested for linkage to VRNF, and if any are very tightly linked to the disorder, they will be intensively analyzed for differences in structure or expression in the disease. DNA markers will be used to compare DNA from VRNF tumors and normal tissue to search for deletions, translocations or rearrangements in chromosome 17, which might allow to further narrow the region containing the VRNF gene. Similarly, we will use markers linked to VRNF to search for chromosomal aberrations, to perform DNA linkage analysis in diseases with symptoms overlapping with those of VRNF, such as the neurofibromatosis-Noonan syndrome and to define the precise chromosomal breakpoint in the VRNF family where the three members all possess a balanced translocation involving 17q. After bracketing the defect to the minimum genetically definable region on chromosome 17 overlapping DNA clones representing this region would be isolated and analyzed to locate the VRNF defect. The cloning and characterization of the VRNF gene should provide important new insights into fundamental of tumor development in VRNF, and possibly in other disorders with a predisposition to tumor development.